Overcoming Challenging Substituent Perturbations with Multisite λ-Dynamics: A Case Study Targeting β-Secretase 1

Area of Science:

• Computational chemistry
• Drug discovery
• Molecular modeling

Background:

• Alchemical free energy calculations are crucial for structure-based drug design.
• They enable in silico exploration of functional group modifications, guiding synthetic strategies.
• Advancements are needed for more efficient and precise computational methods.

Purpose of the Study:

• To evaluate the efficacy of multisite λ-dynamics (MSλD) for exploring large substituent perturbations in drug design.
• To assess MSλD's ability to handle scaffold modifications in β-secretase 1 (BACE1) inhibitors.
• To compare MSλD performance against traditional free energy calculation methods.

Main Methods:

• Utilized MSλD, an innovative alchemical free energy framework.
• Applied the method to a series of 21 BACE1 inhibitors developed by Janssen Pharmaceuticals.
• Performed simultaneous exploration of diverse ligand end-states within a single molecular dynamics (MD) simulation.

Main Results:

• MSλD efficiently explored all structurally diverse ligand end-states simultaneously in a single MD simulation.
• Achieved high precision in predictions, with accuracy within 0.5-0.8 kcal/mol.
• Demonstrated reduced computational costs compared to the TI/MBAR approach.

Conclusions:

• MSλD is a highly precise and computationally efficient method for exploring ligand modifications in drug design.
• The method is force field independent, showing accuracy with CHARMM or OPLS-AA force fields and CM1A charges.
• MSλD presents a viable and advantageous alternative to FEP or TI for structure-based drug design.